One of the most well-known and widely-used classes of antibacterial agents is the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the betalactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Thus, according to the invention, there are provided certain new chemical compounds which are potent inhibitors of microbial beta-lactamases. More specifically, these new chemical compounds are (3S,5R)-penam-3-carboxylic acid 1,1-dioxide, which optionally has a methyl group at the 2-position, and esters of these compounds which are readily hydrolyzable in vivo. Additionally, there is also provided a method for enhancing the effectiveness of beta-lactam antibiotics using said new chemical compounds. Yet further there are provided certain novel intermediates.
1,1-Dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof have been disclosed in U.S. Pat. Nos. 3,197,466 and 3,536,698, and in an article by Guddal et al., in Tetrahedron Letters, No. 9, 381 (1962). Several penicillin derivatives were tested as potential beta-lactamase inhibitors by Chaikovskaya et al., Antibiotiki, 13, 155 (1968); benzylpenicillin 1,1-dioxide was found to be inactive. Harrison et al., in the Journal of the Chemical Society (London), Perkin I, 1772 (1976), have disclosed a variety of penicillin 1,1-dioxides, including methyl phthalimidopenicillinate 1,1-dioxide and methyl 6,6-dibromopenicillanate 1,1-dioxide. A penam derivative having no methyl groups at C-2 is disclosed by Hoogmattens et al., Journal of Medicinal Chemistry, 17, 389 (1974); and penam derivatives with one methyl group at C-2 are disclosed by Claes et al., European Journal of Medicinal Chemistry, Chimica Therapeutica, 10, 573 (1975). Penicillanic acid is known from British Pat. No. 1,072,108.
My copending application Ser. No. 890,451, filed March 29, 1978, discloses and claims compounds of the formula: ##STR1## and the pharmaceutically-acceptable base salts thereof, wherein R is selected from the group consisting of hydrogen, ester-forming residues readily hydrolyzable in vivo, and conventional penicillin carboxy protecting groups. The compounds of the formula I, wherein R is hydrogen or an ester-forming residue readily hydrolyzable in vivo, are useful as antibacterial agents and for enhancing the antibacterial activity of beta-lactam antibiotics. Said compounds of the formula I, wherein R is a penicillin carboxy protecting group, are useful as chemical intermediates to the compound of the formula I, wherein R is hydrogen or an ester-forming residue readily hydrolyzable in vivo.